| 61. |
- Nissen, Klaus B., et al.
(författare)
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Targeting Protein-Protein Interactions with Trimeric Ligands : High Affinity Inhibitors of the MAGUK Protein Family
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- PDZ domains in general, and those of PSD-95 in particular, are emerging as promising drug targets for diseases such as ischemic stroke. We have previously shown that dimeric ligands that simultaneously target PDZ1 and PDZ2 of PSD-95 are highly potent inhibitors of PSD-95. However, PSD-95 and the related MAGUK proteins contain three consecutive PDZ domains, hence we envisioned that targeting all three PDZ domains simultaneously would lead to more potent and potentially more specific interactions with the MAGUK proteins. Here we describe the design, synthesis and characterization of a series of trimeric ligands targeting all three PDZ domains of PSD-95 and the related MAGUK proteins, PSD93, SAP-97 and SAP-102. Using our dimeric ligands targeting the PDZ1-2 tandem as starting point, we designed novel trimeric ligands by introducing a PDZ3-binding peptide moiety via a cysteine-derivatized NPEG linker. The trimeric ligands generally displayed increased affinities compared to the dimeric ligands in fluorescence polarization binding experiments and optimized trimeric ligands showed low nanomolar inhibition towards the four MAGUK proteins, thus being the most potent inhibitors described. Kinetic experiments using stopped-flow spectrometry showed that the increase in affinity is caused by a decrease in the dissociation rate of the trimeric ligand as compared to the dimeric ligands, likely reflecting the lower probability of simultaneous dissociation of all three PDZ ligands. Thus, we have provided novel inhibitors of the MAGUK proteins with exceptionally high affinity, which can be used to further elucidate the therapeutic potential of these proteins.
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| 62. |
- Nordstrand, Annika, et al.
(författare)
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Bone Cell Activity in Clinical Prostate Cancer Bone Metastasis and Its Inverse Relation to Tumor Cell Androgen Receptor Activity
- 2018
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067 .- 1661-6596. ; 19:4
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Tidskriftsartikel (refereegranskat)abstract
- Advanced prostate cancer frequently metastasizes to bone and induces a mixed osteoblastic/osteolytic bone response. Standard treatment for metastatic prostate cancer is androgen-deprivation therapy (ADT) that also affects bone biology. Treatment options for patients relapsing after ADT are limited, particularly in cases where castration-resistance does not depend on androgen receptor (AR) activity. Patients with non-AR driven metastases may, however, benefit from therapies targeting the tumor microenvironment. Therefore, the current study specifically investigated bone cell activity in clinical bone metastases in relation to tumor cell AR activity, in order to gain novel insight into biological heterogeneities of possible importance for patient stratification into bone-targeting therapies. Metastasis tissue obtained from treatment-naive (n = 11) and castration-resistant (n = 28) patients was characterized using whole-genome expression analysis followed by multivariate modeling, functional enrichment analysis, and histological evaluation. Bone cell activity was analyzed by measuring expression levels of predefined marker genes representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST). Principal component analysis indicated a positive correlation between osteoblast and osteoclast activity and a high variability in bone cell activity between different metastases. Immunohistochemistry verified a positive correlation between runt-related transcription factor 2 (RUNX2) positive osteoblasts and tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) positive osteoclasts lining the metastatic bone surface. No difference in bone cell activity was seen between treatment-naive and castration-resistant patients. Importantly, bone cell activity was inversely correlated to tumor cell AR activity (measured as AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2 expression) and to patient serum prostate-specific antigen (PSA) levels. Functional enrichment analysis indicated high bone morphogenetic protein (BMP) signaling in metastases with high bone cell activity and low tumor cell AR activity. This was confirmed by BMP4 immunoreactivity in tumor cells of metastases with ongoing bone formation, as determined by histological evaluation of van Gieson-stained sections. In conclusion, the inverse relation observed between bone cell activity and tumor cell AR activity in prostate cancer bone metastasis may be of importance for patient response to AR and/or bone targeting therapies, but needs to be evaluated in clinical settings in relation to serum markers for bone remodeling, radiography and patient response to therapy. The importance of BMP signaling in the development of sclerotic metastasis lesions deserves further exploration.
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| 63. |
- Nordstrand, Annika, et al.
(författare)
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Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer often metastasizes to bone and the metastases are generally classified as osteoblastic, although a mixed osteoblastic/osteolytic bone response may exist. The present study aimed to characterize the bone remodeling activity in clinical bone metastasis samples, with the overall hypothesis that diversities exist that may be of importance for clinical response to current therapies. Specifically, we aimed to study bone remodeling activity in relation to tumor cell androgen receptor (AR) activity. Metastasis tissue obtained from treatment-naïve (n=11) and castration-resistant (n=28) patients during surgery for spinal cord compression was characterized using whole-genome expression analysis followed by multivariate modeling and functional enrichment analysis as well as by histological evaluation. By analyzing expression levels of a predefined set of markers representing osteoclasts (ACP5, CTSK, MMP9), osteoblasts (ALPL, BGLAP, RUNX2) and osteocytes (SOST), we found high osteoblast activity to be coupled to a high osteoclast activity. Immunohistochemistry verified a significant correlation between RUNX2 positive osteoblasts and TRAP (ACP5) positive osteoclasts lining metastatic bone surfaces in close contact to tumor cells. No difference in bone remodeling activity was seen between treatment naïve and castration-resistant patients, while the bone remodeling activity was inversely correlated to AR activity within the tissue (measured as expression of the AR, FOXA1, HOXB13, KLK2, KLK3, NKX3-1, STEAP2, and TMPRSS2) and patient serum PSA levels. Ontology analysis suggested enriched BMP signaling in metastases with high bone remodeling activity and, accordingly, BMP4 mRNA expression was significantly higher in bone metastases with than without ongoing bone formation, as determined from histological evaluation of van Gieson-stained sections. In conclusion, we have observed diversities in bone remodeling activity among clinical samples of prostate cancer bone metastases that may be of importance when selecting therapy for patients with bone metastatic cancer, especially when bone-targeting therapies are considered. The importance of the BMP signaling system for the development of sclerotic metastasis lesion deserve further exploration.
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| 64. |
- Nozohoor, Shahab, et al.
(författare)
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ABO blood group does not impact incidence or outcomes of surgery for acute type A aortic dissection
- 2020
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Ingår i: Scandinavian Cardiovascular Journal. - : Taylor & Francis. - 1401-7431 .- 1651-2006. ; 54:2, s. 124-129
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate the distribution and impact of ABO blood groups on postoperative outcomes in patients undergoing surgery for acute type A aortic dissection (ATAAD).Design: A total of 1144 surgical ATAAD patients from eight Nordic centres constituting the Nordic consortium for acute type A aortic dissection (NORCAAD) were analysed. Blood group O patients were compared to non-O subjects. The relative frequency of blood groups was assessed with t-distribution, modified for weighted proportions. Multivariable logistic regression was performed to identify independent predictors of 30-day mortality. Cox regression analyses were performed for assessing independent predictors of late mortality.Results: There was no significant difference in the proportions of blood group O between the study populations in the NORCAAD registry and the background population (40.6 (95% CI 37.7-43.4)% vs 39.0 (95% CI 39.0-39.0)%). ABO blood group was not associated with any significant change in risk of 30-day or late mortality, with the exception of blood group A being an independent predictor of late mortality. Prevalence of postoperative complications was similar between the ABO blood groups.Conclusions: In this large cohort of Nordic ATAAD patients, there were no associations between ABO blood group and surgical incidence or outcomes, including postoperative complications and survival.
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| 65. |
- Oudin Åström, Daniel, et al.
(författare)
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Temperature effects on incidence of surgery for acute type A aortic dissection in the Nordics
- 2022
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Ingår i: Global health action. - : Informa UK Limited. - 1654-9880 .- 1654-9880 .- 1654-9716. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to investigate a hypothesised association between daily mean temperature and the risk of surgery for acute type A aortic dissection (ATAAD). For the period of 1 January 2005 until 31 December 2019, we collected daily data on mean temperatures and date of 2995 operations for ATAAD at 10 Nordic cities included in the Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) collaboration. Using a two-stage time-series approach, we investigated the association between hot and cold temperatures relative to the optimal temperature and the rate of ATAAD repair in the selected cities. The relative risks (RRs) of cold temperatures (<=-5 degrees C) and hot temperatures (>= 21 degrees C) compared to optimal temperature were 1.47 (95% CI: 0.72-2.99) and 1.43 (95% CI: 0.67-3.08), respectively. In line with previous studies, we observed increased risk at cold and hot temperatures. However, the observed associations were not statistically significant, thus only providing weak evidence of an association.
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| 66. |
- Pan, E., et al.
(författare)
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Low rate of reoperations after acute type A aortic dissection repair from The Nordic Consortium Registry
- 2018
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Ingår i: Journal of Thoracic and Cardiovascular Surgery. - : Elsevier BV. - 0022-5223 .- 1097-685X. ; 156:3, s. 939-948
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To describe the relationship between the extent of primary aortic repair and the incidence of reoperations after surgery for type A aortic dissection. Methods: A retrospective cohort of 1159 patients treated for type A aortic dissection at eight Nordic low-to medium-sized cardiothoracic centers from 2005 to 2014. Data were gathered from patient records and national registries. Patients were separately divided into 3 groups according to the distal anastomoses technique (ascending aorta [n = 791], hemiarch [n = 247], and total arch [n = 66]), and into 2 groups for proximal repair (aortic root replacement [n = 285] and supracoronary repair [n = 832]). Freedom from reoperation was estimated with cumulative incidence survival and Fine-Gray competing risk regression model was used to identify independent risk factors for reoperation. Results: The median follow-up was 2.7 years (range, 0-10 years). Altogether 51 out of 911 patients underwent reoperation. Freedom from distal reoperation at 5 years was 96.9%, with no significant difference between the groups (P = .22). Freedom from proximal reoperation at 5 years was 97.8%, with no difference between the groups (P = .84). Neither DeBakey classification nor the extent of proximal or distal repair predicted freedom from a later reoperation. The only independent risk factor associated with a later proximal reoperation was a history of connective tissue disease. Conclusions: Type A aortic dissection repair in low-to medium-volume centers was associated with a low reoperation rate and satisfactory midterm survival. The extent of the primary repair had no significant influence on reoperation rate or midterm survival.
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| 67. |
- Pärssinen, Varpu, et al.
(författare)
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Variation in predation regime drives sex-specific differences in mosquitofish foraging behaviour
- 2021
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Ingår i: Oikos. - : Wiley-Blackwell. - 0030-1299 .- 1600-0706. ; 130:5, s. 790-797
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Tidskriftsartikel (refereegranskat)abstract
- Predation is a well-studied driver of ecological selection on prey traits, which frequently drives divergence in anti-predator performance across environments that vary in predation risk. However, predation also alters prey mortality regimes, where low predation risk often results in higher prey densities and consequently higher intensities of intraspecific resource competition. In addition, predation risk alters the foraging context, as acquiring food can be risky in the presence of predators. Thus, different predation regimes can drive divergent selection on traits associated with resource competition, such as foraging behaviours. Moreover, because sexes often differ in susceptibility to predation and limitations to their reproductive output, the intensity of the tradeoff between predator avoidance and resource competition may depend on sex. We used a laboratory experiment to assess key aspects of foraging performance in a predator-free context in Bahamas mosquitofish Gambusia hubbsi wild-caught from multiple populations that experience either high or low levels of predation risk. When competing for limited food resources at a common density, females from low-predation regimes showed higher foraging and food consumption rates than females from high-predation regimes. Males showed fewer differences between predation regimes, and an opposite pattern from females. We suggest these sex-specific effects result from females facing a greater tradeoff between predation risk and resource competition, combined with males from high-predation environments elevating foraging behaviours in the absence of nearby predators and females. Females of this species are larger than males, bear live young and show higher foraging rates in the wild than males. On the other hand, males spend more time pursuing females in the wild, and may exhibit greater flexibility in foraging behaviours based on the immediate context. Our results show that varying levels of predation risk can lead to differences in behaviours associated with resource competition, but these effects can strongly differ between sexes.
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| 68. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 69. |
- Semb, Gunvor, et al.
(författare)
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A Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 1. Planning and management.
- 2017
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - : Taylor & Francis. - 2000-656X .- 2000-6764. ; 51:1, s. 2-13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Longstanding uncertainty surrounds the selection of surgical protocols for the closure of unilateral cleft lip and palate, and randomised trials have only rarely been performed. This paper is an introduction to three randomised trials of primary surgery for children born with complete unilateral cleft lip and palate (UCLP). It presents the protocol developed for the trials in CONSORT format, and describes the management structure that was developed to achieve the long-term engagement and commitment required to complete the project.METHOD: Ten established national or regional cleft centres participated. Lip and soft palate closure at 3-4 months, and hard palate closure at 12 months served as a common method in each trial. Trial 1 compared this with hard palate closure at 36 months. Trial 2 compared it with lip closure at 3-4 months and hard and soft palate closure at 12 months. Trial 3 compared it with lip and hard palate closure at 3-4 months and soft palate closure at 12 months. The primary outcomes were speech and dentofacial development, with a series of perioperative and longer-term secondary outcomes.RESULTS: Recruitment of 448 infants took place over a 9-year period, with 99.8% subsequent retention at 5 years.CONCLUSION: The series of reports that follow this introductory paper include comparisons at age 5 of surgical outcomes, speech outcomes, measures of dentofacial development and appearance, and parental satisfaction. The outcomes recorded and the numbers analysed for each outcome and time point are described in the series.TRIAL REGISTRATION: ISRCTN29932826.
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| 70. |
- Svensson, Emma M., 1979-, et al.
(författare)
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Coat colour and sex identification in horses from Iron Age Sweden
- 2012
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Ingår i: Annals of Anatomy. - : Elsevier BV. - 0940-9602 .- 1618-0402. ; 194:1, s. 82-87
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Tidskriftsartikel (refereegranskat)abstract
- Domestication of animals and plants marked a turning point in human prehistory. To date archaeology, archaeozoology and genetics have shed light on when and where all of our major livestock species were domesticated. Phenotypic changes associated with domestication have occurred in all farm animals. Coat colour is one of the traits that have been subjected to the strongest human selection throughout history. Here we use genotyping of coat colour SNPs in horses to investigate whether there were any regional differences or preferences for specific colours associated with specific cultural traditions in Iron Age Sweden. We do this by identifying the sex and coat colour of horses sacrificed at Skedemosse, Oland (Sweden) during the Iron Age, as well as in horses from two sites in Uppland, Ultuna and Valsgarde (dated to late Iron Age). We show that bay, black and chestnut colours were all common and two horses with tobiano spotting were found. We also show how the combination of sex identification with genotyping of just a few SNPs underlying the basic coat colours can be used to identify the minimum number of individuals at a site on a higher level than morphological methods alone. Although separated by 500 km and from significantly different archaeological contexts the horses at Skedemosse and Ultuna are quite homogenous when it comes to coat colour phenotypes, indicating that there were no clear geographical variation in coat colouration in Sweden during the late Iron Age and early Viking Age.
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